The present invention relates to a novel lyophilized composition containing cyclophosphamide and sodium bicarbonate as an excipient.
U.S. Pat. No. 4,537,883 to Alexander et al. (Mead Johnson & Co.) discloses various lyophilizates of cyclophosphamide. These lyophilizates are prepared by lyophilizing a solution of cyclophosphamide and one or more excipients and re-hydrating the product such that it contains about 4% moisture. The patent is based upon a comparative study of lyophilizate cakes and the dissolution time for lyophilizates of cyclophosphamide prepared using a number of excipients. The study concludes that the lyophilizate prepared with mannitol gives a better cake and faster dissolution time than the lyophilizates prepared with other excipients. The patent also teaches that the lyophilized cyclophosphamide-mannitol composition exhibits better thermal stability if it contains an equimolar amount of water based on cyclophosphamide. The preferred lyophilizate contains 20 parts cyclophosphamide, 1.25 to 2 parts water and 10 to 85 parts mannitol. Among the excipients evaluated in the patent are mannitol, sodium bicarbonate, lactose, polyvinyl pyrrolidone (PVP), arginine, and tartaric acid. The lyophilizates illustrated in the patent prepared with sodium bicarbonate exhibited dissolution times upon reconstitution of about two minutes or greater.
A study of "The Stability of Cyclophosphamide in Lyophilized Cakes" by Kovalcik and Guillory, J. Parenteral Science & Technology, 42, No. 1, 29-37 (1988) discloses sodium bicarbonate lyophilizates prepared using a 1:4 weight ratio of cyclophosphamide to sodium bicarbonate with a 5% water content of total weight of the lyophilizate. The sample cakes showed a 5% loss in potency when left at room temperature for 53 days and 4% loss in potency when stored at room temperature for 117 days.
Practical problems have occurred preparing a composition having a 1:4 ratio of cyclophosphamide to sodium bicarbonate in that special large vial sizes are required to obtain a lyophilizate cake. In addition, the solids of such ratios are not readily soluble and hydration time is undesirably long due to high sodium bicarbonate concentration and the amount of water necessary is greater than the sum of the mole equivalent of cyclophosphamide and the mole equivalent sodium bicarbonate.
It has also been unknown that pH levels should be kept at 8 or above in the lyophilization process in order to achieve a highly stable cake. When the pH of the bulk solution drops below 8, carbon dioxide is undesirably released and causes a reduction in effective concentration of sodium carbonate in the solution for lyophilization and adversely affects stability of the cake.